Aging and age-related diseases are both fields of intense interest for public health and basic biological study. While we have seen great progress in identifying the pathways that regulate aging, as well as increasing understanding of the fundamental causes of age-related diseases, the connections between the two bodies of literature are often not explicit. We have recently identified a role for the transcription factor NRSF/REST in a late-life, neuron-specific stress response, the integrity of which appears to delineate healthy brain aging vs. pathological deterioration of neurons in late life. We have shown that this activity is conserved in the C. elegans suppressor of presenilin (spr) family of genes. In this proposal, we have identified a role for these genes in regulating insulin/IGF signaling, a pathway that is known to be critically important for aging. The experiments proposed in this application aim to utilize both C. elegans and mammalian models to explore the connections between REST and insulin/IGF signaling, and understand how their interaction promotes neuronal stress resistance. Doing so will allow us to connect the age-related induction of REST in human neurons to the prolific data on insulin/IGF regulation of aging, and shed light on how these interactions promote healthy aging and prevent neurodegenerative disease. I will work toward these goals under the mentorship of Dr. Bruce Yankner, a long-standing expert in brain aging and neurodegenerative disease. His lab is located in Harvard Medical School, an excellent scientific environment that will provide me with expertise and advice as needed. The funds provided will allow me to direct the last years of my postdoctoral career utilizing a multidisciplinary approach consisting of powerful genetics and biochemistry in multiple model systems to characterize a novel regulator of aging pathology. These tools and expertise will be critical in starting my own lab, which will apply them to incisive experiments geared towards understanding the connections between human aging and disease.